Systems and methods for transfer of ions for analysis

ABSTRACT

The invention generally relates to systems and methods for transferring ions for analysis. In certain embodiments, the invention provides a system for analyzing a sample including an ionizing source for converting molecules of a sample into gas phase ions in a region at about atmospheric pressure, an ion analysis device, and an ion transfer member operably coupled to a gas flow generating device, in which the gas flow generating device produces a laminar gas flow that transfers the gas phase ions through the ion transfer member to an inlet of the ion analysis device.

RELATED APPLICATION

The present application is a continuation of U.S. nonprovisionalapplication Ser. No. 14/594,217, filed Jan. 12, 2015, which is acontinuation of U.S. nonprovisional application Ser. No. 14/454,811,filed Aug. 8, 2014, which is a continuation of U.S. nonprovisionalapplication Ser. No. 14/180,915, filed Feb. 14, 2014, which is acontinuation of U.S. nonprovisional application Ser. No. 13/937,913,filed Jul. 9, 2013, which is a continuation of U.S. nonprovisionalapplication Ser. No. 13/727,840 filed Dec. 27, 2012, which is acontinuation of U.S. nonprovisional application Ser. No. 13/122,651,filed Jun. 20, 2011, which is a 371 national phase application andclaims the benefitof and priority to PCT/US09/59514, filed Oct. 5, 2009,which PCT application claims the benefit of and priority to U.S.provisional patent application Ser. No. 61/104,793, filed Oct. 13, 2008,the content of each of which is incorporated herein by reference in itsentirety.

GOVERNMENT SUPPORT

This invention was made with government support under 2007-ST-069-TSL001awarded by Department of Homeland Security and N000140510454 awarded byU.S. Navy Office of Naval Research. The government has certain rights inthe invention.

TECHNICAL FIELD

The invention generally relates to systems and methods for transfer ofions for analysis.

BACKGROUND

In the field of analytical chemistry, the demand for direct samplingunder ambient conditions has increased, and this has led to thedevelopment of a variety of ambient ionization sources. Ambientionization sources ionize analytes in the ambient environment (in situ)with no intrinsic requirement for sample preparation. This advantageallows real-time, on-site detection, saving time and resources.

A typical set-up that uses an ambient ionization source to analyze ionsfrom a sample is configured such that the ionization source is uncoupledfrom a mass analyzer, such as a mass spectrometer (MS). The massspectrometer must be located sufficiently close to the ionization source(on the order of about 2 cm or less) so that the ions that are generatedwill transfer to an inlet of the mass spectrometer. The opening of theMS inlet is typically smaller than 700 μm, due to the fact that a vacuummust be maintained inside a manifold where ions are mass analyzed. Inapplications in which the ions are generated far from the MS inlet (onthe order of about 5 cm), it is difficult, if not impossible, totransfer the ions to the mass analyzer. Thus the distance between theambient ionization source and the mass analyzer limits the use of theseambient ionization sources.

Further, the ions generated from an ionization source at atmosphericpressure, such as an electrospray ionization (ESI) or desorptionelectrospray ionization (DESI), also have a wide angular dispersion. Theintake of the ions by the MS inlet of a small opening is relativelyinefficient. In an application in which analytes over a large area needto be analyzed or monitored simultaneously, it is highly desirable thatthe ions generated be transferred into the MS inlet at high efficiency.

There is a need for devices that can facilitate transfer of ions from anambient ionization source to an inlet of a mass spectrometer.

SUMMARY

The invention provides systems that use a gas flow to bring ions into aconfined space and generate a laminar gas flow that focuses the ions andfacilitates transfer of the ions from an ambient ionization source to aninlet of an ion analysis device, such as a mass spectrometer. Systems ofthe invention allow for transfer of ions over long distances (e.g., atleast about 5 cm), and also allow for sampling over large areas (e.g.,at least about areas of 4 cm×3 cm or 10 cm×10 cm). For example, systemsof the invention allow for use of ambient ionization sources underconditions in which the ionization source cannot be positionedsufficiently close to an inlet of an ion analysis device for collectionof ions generated from a sample.

An aspect of the invention provides a system for analyzing a sampleincluding an ionizing source for converting molecules of a sample intogas phase ions in a region at about atmospheric pressure, an ionanalysis device, and an ion transfer member operably coupled to a gasflow generating device, in which the gas glow generating device producesa laminar gas flow that transfers the gas phase ions through the iontransfer member to an inlet of the ion detection device.

A typical prior art set-up that uses an ambient ionization sourcepositions the ionization source about 2 cm or closer to the inlet of theion analysis device. Distances greater than 2 cm between the ionizationsource and the inlet of the ion analysis device result in diffusion ofions into the atmosphere and degradation of signal, i.e., inefficient orno transfer of ions to the ion analysis device. Systems and methods ofthe invention generate a laminar gas flow, thus allowing for efficienttransfer of ions over long distances without significant loss of signalintensity, such as distances of at least about 5 cm, at least about 10cm, at least about 20 cm, at least about 50 cm, at least about 100 cm,at least about 500 cm, at least about 1 m, at least about 3 m, at leastabout 5 m, at least about 10 m, and other distances.

In certain embodiments, the ion analysis device is a mass spectrometer.In other embodiments, the ion analysis device is an ion mobilityspectrometer. In other embodiments, the ion analysis device is a simpleion detector such as a Faraday cup. In certain embodiments, the ions aredetected or analyzed after transfer. In other embodiment, the ions arere-collected after transfer.

In certain embodiments, the gas flow generating device is a pump havinga high flow rate and a low compression ratio, such as a house vacuum,that is connected to the ion transfer member to produce a laminar gasflow for transfer of ions to the inlet of the ion analysis device. Inother embodiments, the gas flow generating device is the ambientionization source. For example, a source used for desorptionelectrospray ionization (DESI) generates a gas flow sufficient toproduce a laminar flow through the ion transfer member, and thusproduces a laminar gas flow that transfers the gas phase ions to aninlet of the ion analysis device. In other embodiments, the gas flowgenerating device is a combination of the pump and the gas jet of theambient ionization source.

The system may further include an electric focusing lens device operablycoupled to the ion transfer member to facilitate transfer of ions to theinlet of the ion analysis device. The system may further include an airdynamic lens device operably coupled to the ion transfer member tofacilitate focusing of heavy ions to the inlet of the ion analysisdevice. The system may further include an electro-hydrodynamic lensdevice operably coupled to the ion transfer member. The system mayfurther include at least one vacuum pump connected to the ion detectiondevice. The system may further include a computer operably connected tothe system. The system may further include a stage for holding thesample.

In certain embodiments, the ion transfer member is coupled with adielectric barrier discharge to enhance ion transfer efficiency. Inother embodiments, a distal end of the ion transfer member includes aplurality of inlets for transferring ions from multiple locations to theinlet of the ion analysis device.

The ion transfer member may be any connector that allows for productionof a laminar flow within it and facilitates transfer of ions withoutsignificant loss of ion current. An exemplary ion transfer member is atube. The tube may be composed of rigid material, such as metal orglass, or may be composed of flexible material such as TYGON tubing. Theion transfer member may be any shape as long the shape allows forproduction of a laminar flow within it and facilitates transfer of ionswithout significant loss of ion current. For example, the ion transfermember may have the shape of a straight line. Alternatively, the iontransfer member may be curved or have multiple curves.

The ionizing source may operate by any technique that is capable ofconverting molecules of a sample into gas phase ions at substantiallyatmospheric pressure, i.e., an atmospheric pressure ionization source oran ambient ionization source. Exemplary techniques include electrosprayionization, nano-electrospray ionization, atmospheric pressurematrix-assisted laser desorption ionization, atmospheric pressurechemical ionization, desorption electrospray ionization, atmosphericpressure dielectric barrier discharge ionization, atmospheric pressurelow temperature plasma desorption ionization, and electrospray-assistedlaser desorption ionization.

The ions generated from the ionization source are sent through the iontransfer member and are transferred to an inlet of an ion analysisdevice. Exemplary ion analysis devices include a mass spectrometer, andan ion mobility spectrometer. Exemplary mass spectrometers include anion trap, a quadrupole filter, a time of flight, a sector, an ioncyclotron resonance trap, and an orbitrap mass spectrometer.

Systems of the invention may analyze samples in any state, e.g., solidphase, liquid phase, or gas phase. The sample may be of any origin, suchas a biological origin or a non-biological origin. Exemplary samplesinclude an industrial work piece, a pharmaceutical product oringredient, a food or food ingredient, a toxin, a drug, an explosive, abacterium, or a biological tissue or fluid.

Another aspect of the invention provides a method of analyzing a sampleincluding ionizing a sample to convert molecules of the sample into gasphase ions in a region at about atmospheric pressure, providing an iontransfer member coupled to a gas flow generating device to produce alaminar gas flow that transfers the gas phase ions to an inlet of theion analysis device, and analyzing the ions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic showing an embodiment of a system for transferringions from an ambient ionization source to an inlet of an ion analysisdevice.

FIG. 2 is a photograph showing a setup for long distance ion transfer.

FIG. 3 is a tandem mass spectrum of 1.7 μg cocaine on glassdesorbed/ionized via LTP helium and transferred 4 ft using a flexibleTYGON tubing.

FIG. 4 is a tandem mass spectrum of 2 μg of TNT on glassdesorbed/ionized via LTP helium and transferred 4 ft using a flexibleTYGON tubing.

FIG. 5 is a tandem mass spectrum of 1.7 μg cocaine on glassdesorbed/ionized via LTP helium and transferred 10 ft in stainless steel¾″ diameter conduit.

FIG. 6 is a photograph showing a setup for long distance ion transferusing large area analysis via LTP probes.

FIG. 7A is a photograph showing an LTP large area sampling funnel(area=33 cm²) with four LTP probes coupled with long distance iontransfer instrumentation. FIG. 7B is a total ion chronogram of m/z 226transferred 4 ft, showing when funnel is over 2 μg of TNT on glassslide.

FIG. 8 is a schematic showing that ions generated from samples atmultiple locations can be transferred to mass spectrometer for analysis,simultaneously or in a sequence.

FIG. 9 is a schematic showing a tube electric lens that can beimplemented to focus the charged particles toward the center of thetransfer tubing.

FIG. 10 is a schematic showing an electro-air dynamic lens system thatcan be implemented to use the air dynamic effects to focus the heavierparticles and to use the electric field to focus the charged particlestoward the center.

FIG. 11A is a schematic of a dielectric barrier discharge (DBD) tubing.FIG. 11B is a photograph showing DBD tubing made with double strandspeaker wire. FIG. 11C is a photograph showing the DBD inside the tubingwith high voltage AC applied.

FIG. 12 is a schematic showing a desorption electrospray ionization(DESI) long distance transport setup.

FIG. 13 is a graph showing variation of TIC with sampling distance. Arhodamine ink spot was used as analyte. It was observed that signal fallrate decreases beyond 40 mm. A fully developed laminar flow could begenerated between 40 mm and 50 mm downstream in the drift tube.

FIG. 14 is a diagram showing a CFD simulation, indicating fullydeveloped laminar flow is achieved at around 55 mm.

FIG. 15 is a mass spectrum of 10 pg of cocaine detected on a glassslide, 10 cm away from the MS inlet using the device shown in FIG. 12.The MS/MS spectrum is shown in the inset. An LTQ (Thermo FisherScientific) mass spectrometer was used

FIG. 16 is a set of mass spectra for different drift tubes showingdifferences in relative intensities of analyte vs. background signalintensities. Spectra were collected using the device shown in FIG. 12and an LTQ mass spectrometer

FIG. 17 is a schematic of the large area sampling configuration with aDESI source.

FIG. 18 is a diagram showing a configuration of an experiment with alarge area sampling DESI source.

FIG. 19 is a mass spectrum corresponding to position 1 for a large areasampling DESI source.

FIG. 20 is a graph showing peak signal intensities achieved with eachtransfer tube in DESI configuration.

FIG. 21 is a set of mass spectra showing cocaine detected on a Mini 10instrument with a DESI focusing source.

FIG. 22 is a schematic diagram of showing an LTP probe and a miniaturemass spectrometer with a discontinuous atmospheric pressure interfacecoupled through an ion transfer member and a gas flow generating device.

FIGS. 23A-D shows a typical spectra of melamine in different matricesusing LTP/Mini 10.5. FIG. 23A shows an MS spectrum of 300 ng/mL melaminein water/methanol (v:v=1:1), loading volume 3 μL (absolute melamineamount of 0.9 ng). FIG. 23B shows an MS spectrum of 5 μg/mL melamine inwhole milk, loading volume 3 μL (absolute melamine amount of 15 ng).FIG. 23C shows an MS spectrum of 5 μg/g melamine in milk powder, loadingvolume 5 mg (absolute melamine amount of 25 ng). FIG. 23D shows an MSspectrum of 1 μg/mL melamine in synthetic urine, loading volume 3 μL(absolute melamine amount of 3 ng). Inserts: MS/MS product ion spectrumof the protonated molecule.

DETAILED DESCRIPTION

A typical prior art set-up that uses an ambient ionization sourcepositions the ionization source about 2 cm or closer to the inlet of theion analysis device. The transfer of the ion into the inlet of a massspectrometer relies on the gas flow into the inlet under the influenceof the vacuum of the spectrometer and the electric field in thesurrounding area. The gas flow is typically low due to the lowconductance of the inlet, which serve as the conductance barrier betweenatmosphere and vacuum manifold. Distances greater than 2 cm between theionization source and the inlet of the ion analysis device result indiffusion of ions into the atmosphere and degradation of signal, i.e.,inefficient or no transfer of ions into the ion analysis device. Systemsand methods of the invention generate a laminar gas flow that allows forefficient transfer of ions without significant loss of signal intensityover longer distances, such as distances of at least about 5 cm, atleast about 10 cm, at least about 20 cm, at least about 50 cm, at leastabout 100 cm, at least about 500 cm, at least about 1 m, at least about3 m, at least about 5 m, at least about 10 m, and other distances.

Systems and methods of the invention are useful for chemical analysis insituations in which it is important for the instrument and the objectbeing examined to be in different locations. For example, systems andmethods herein are useful for screenings at security checkpoints, e.g.,airport security checkpoints or road-side checkpoints, for interrogationof luggage surfaces for the detection of foreign substances.

An aspect of the invention provides a system for analyzing a sampleincluding an ionizing source for converting molecules of a sample intogas phase ions in a region at about atmospheric pressure, an ionanalysis device, and an ion transfer member operably coupled to a gasflow generating device, in which the gas flow generating device producesa laminar gas flow that transfers the gas phase ions to an inlet of theion analysis device.

Systems of the invention provide enlarged flow to carry ions from adistant sample to an inlet of an ion analysis device, such as an inletof a mass spectrometer. The basic principle used in the transport deviceis the use of the gas flow to direct gas and ions into the ion transfermember and to form a laminar flow inside the ion transfer member to keepthe ions away from the walls while transferring the gas and ions throughthe ion transfer member. The analyte ions of interest are sampled atsome point downstream along the ion transfer member. The laminar flow isachieved by balancing the incoming and outgoing gas flow. Thusrecirculation regions and/or turbulence are avoided. Thus, the generatedlaminar flow allows for high efficient ion transport over long distanceor for sampling of ions over large areas.

Systems of the invention also provide enlarged flow to carry ions fromthe ion source to an inlet of a miniature mass spectrometer, which hassmall pumping systems and compromised gas intake capability at theinlet. Additional gas flow provided by a miniature sample pump connectedwith the ion transfer member facilitates ion transfer from an ambientionization source to the vicinity of the inlet of the miniature massspectrometer. Thus the intensity of the ions for the analytes ofinterest is increased for mass analysis.

As shown in FIG. 1, an ion transfer member, e.g., a tube with an innerdiameter of about 10 mm or greater, is used to transfer ions from theionization source to the inlet of an ion analysis device, e.g., a massspectrometer. The larger opening of the ion transfer member, as comparedto the opening of the inlet of the ion analysis device, is helpful forcollection of sample ions generated in a large space, e.g. on a surfaceof large area. The large flow conductance of the ion transfer memberallows the gas carrying ions to move toward the inlet of the ionanalysis device at a fast flow rate. The ion transfer member is coupledto a gas flow generating device. The gas flow generating device producesa gas flow inside the ion transfer member. The inlet of the ion analysisdevice receives the ions transferred from the ambient ionization source.

The ion transfer member may be any connector that allows for productionof a laminar flow within it and facilitates transfer of ions withoutsignificant loss of ion current. Exemplary ion transfer members includetubes, capillaries, covered channels, open channels, and others. In aparticular embodiment, the ion transfer member is a tube. The iontransfer member may be composed of rigid material, such as metal orglass, or may be composed of flexible material such as plastics,rubbers, or polymers. An exemplary flexible material is TYGON tubing.

The ion transfer member may be any shape as long the shape allows forthe production of a flow to prevent the ions from reaching the internalsurfaces of the ion transfer member where they might become neutral. Forexample, the ion transfer member may have the shape of a straight line.Alternatively, the ion transfer member may be curved or have multiplecurves.

The ion transfer member is coupled to a gas flow generating device. Thegas flow generating device is such a device capable of generating a gasflow through the ion transfer member. The gas flow generating devicefacilitates transfer of the ions from the ambient ionization source tothe inlet of the ion analysis device. In certain embodiments, the gasflow generating device is a pump with a high flow rate and a lowcompression ratio. An example of such a pump is that found in a shopvacuum or a small sample pump. The proper pumps used for the couplingare different from those used for a mass spectrometer, e.g. a rotaryvane pump or a turbo molecular pump, which pumps have a high compressionratio. The high compression ratio pumps of a mass spectrometer cannot beconnected to the atmosphere through an opening of the conductancedescribed here. For example, Cotte-Rodríguez et al. (Chem. Commun.,2006, 2968-2970) describe a set-up in which the inlet of the massspectrometer was elongated and gas flow generated by the pump inside amass spectrometer was used to transfer ions over a distance up to 1 m.The ions were transferred from the atmosphere to a region at about 1torr. A significant loss in signal occurred for the transfer of the ionsusing the set-up described in Cotte-Rodríguez, and ions generated over alarge area could not be efficiently collected into the inlet.

In other embodiments, the gas flow generating device is the ambientionization source. For example, a source used for desorptionelectrospray ionization (DESI) generates a gas flow sufficient toproduce a laminar flow through the ion transfer member, and thusproduces a laminar gas flow that transfers the gas phase ions over along distance to an inlet of the ion analysis device.

Numerous additional devices may be coupled with the ion transfer memberto further facilitate transfer of the ions from the ambient ionizationsource to the inlet of the ion analysis device. For example, an electriclens may be used to focus the ions toward the center of the ion transfermember while the gas flow generating device pumps away neutral gases(See FIG. 9). In other embodiments, an electro-hydrodynamic lens systemmay be implemented to use the air dynamic effects to focus the heavierparticles and to use the electric field to focus the charged particlestoward the center of the ion transfer member (See FIG. 10).

In other embodiments, a distal end of the ion transfer member mayinclude a plurality of inlets for transferring ions from multiplelocations to the inlet of the ion analysis device. FIG. 8 is a schematicshowing that ions generated from samples at multiple locations can betransferred to a mass spectrometer for analysis, in a simultaneous orsequential fashion.

In still other embodiments, the ion transfer member includes additionalfeatures to prevent ions from being adsorbed onto the inside wall. Asshown in FIG. 11, a dielectric barrier discharge (DBD) tubing is madefrom a double stranded speaker wire. The insulator of the wire serves asthe dielectric barrier and the DBD occurs when high voltage AC isapplied between the two strands of the wire. The DBD inside the tubeprevents the ions from adsorbing onto the wall and provide acharge-enriched environment to keep the ions in the gas phase. This DBDtube can also be used for ionizing the gas samples while transferringthe ions generated to the inlet of the ion analysis device. The DBD tubecan also be used for ion reactions while transferring the ions generatedto the inlet of the ion analysis device.

Prior to entering the ion transfer member, ions of the sample areionized using an ambient ionization source or an atmospheric pressureionization source. Exemplary ambient ionization techniques includeelectrospray ionization (Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S.F.; Whitehouse, C. M. Science 1989, 246, 64-71; Yamashita, M.; Fenn, J.B. J. Phys. Chem. 1984, 88, 4451-4459), nano-electrospray ionization(Karas et al., Fresenius J Anal Chem, 366:669-676, 2000), atmosphericpressure matrix-assisted laser desorption ionization (Laiko, V. V.;Baldwin, M. A.; Burlingame, A. L. Anal. Chem. 2000, 72, 652-657; andTanaka, K.; Waki, H.; Ido, Y.; Akita, S.; Yoshida, Y.; Yoshida, T.;Matsuo, T. Rapid Commun. Mass Spectrom. 1988, 2, 151-153), atmosphericpressure chemical ionization (Carroll, D. L; Dzidic, L; Stillwell, R.N.; Haegele, K. D.; Horning, E. C. Anal. Chem. 1975, 47, 2369-2373),desorption electrospray ionization (Takats et al., U.S. Pat. No.7,335,897; and Takats, Z.; Wiseman, J. M.; Gologan, B.; Cooks, R. G.Science 2004, 306, 471-473), atmospheric pressure dielectric barrierdischarge ionization (Shiea, J.; Huang, M. Z.; Hsu, H. J.; Lee, C. Y.;Yuan, C. H.; Beech, L; Sunner, J. Rapid Commun. Mass Spectrom. 2005, 19,3701-3704), atmospheric pressure low temperature plasma desorptionionization (Ouyang et al. International patent publication WO2009/102766), and electrospray-assisted laser desorption ionization(Shiea, J.; Huang, M. Z.; Hsu, H. J.; Lee, C. Y.; Yuan, C. H.; Beech, L;Sunner, J. Rapid Commun. Mass Spectrom. 2005, 19, 3701-3704). The ionsof the sample then move through the ion transfer member.

After moving through the ion transfer member, the ions are thenseparated based on their mass/charge ratio or their mobility or boththeir mass/charge ratio and mobility. For example, the ions can beaccumulated in an ion analysis device such as a quadrupole ion trap(Paul trap), a cylindrical ion trap (Wells, J. M.; Badman, E. R.; Cooks,R. G., Anal. Chem., 1998, 70, 438-444), a linear ion trap (Schwartz, J.C.; Senko, M. W.; Syka, J. E. P., J. Am. Soc. Mass Spectrom, 2002, 13,659-669), an ion cyclotron resonance (ICR) trap, an orbitrap (Hu et al.,J. Mass. Spectrom., 40:430-433, 2005), a sector, or a time of flightmass spectrometer. Additional separation might be based on mobilityusing ion drift devices or the two processes can be integrated.

Systems of the invention can analyze samples in any state, e.g., solidphase, liquid phase, or gas phase. The sample may be of any origin, suchas a biological origin or a non-biological origin. Exemplary samplesinclude an industrial work piece, a pharmaceutical product oringredient, a food or food ingredient, a toxin, a drug, an explosive, abacterium, or a biological tissue or fluid.

A sample can be from a mammal, e.g. a human tissue or body fluid. Atissue is a mass of connected cells and/or extracellular matrixmaterial, e.g. skin tissue, nasal passage tissue, CNS tissue, neuraltissue, eye tissue, liver tissue, kidney tissue, placental tissue,mammary gland tissue, gastrointestinal tissue, musculoskeletal tissue,genitourinary tissue, bone marrow, and the like, derived from, forexample, a human or other mammal and includes the connecting materialand the liquid material in association with the cells and/or tissues. Abody fluid is a liquid material derived from, for example, a human orother mammal. Such body fluids include, but are not limited to, mucous,blood, plasma, serum, serum derivatives, bile, phlegm, saliva, sweat,amniotic fluid, mammary fluid, and cerebrospinal fluid (CSF), such aslumbar or ventricular CSF. A sample may also be a fine needle aspirateor biopsied tissue. A sample also may be media containing cells orbiological material.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

EXAMPLES Example 1 Long Distance Ion Transfer

A Thermo Scientific LTQ was modified to allow long distance ion transfervia assisted vacuum from an external low temperature plasma (LTP)source. The modified Ion Max source (ion source for LTQ massspectrometer, ThermoFisher, San Jose, Calif.) was used to guide the ionsfrom long distances into the inlet of the LTQ mass spectrometer. Acommon shop vacuum was used as a vacuum device to provide the assistedflow to carry the ions over long distances. The setup used is shown inFIG. 2. An adjustable inlet tube that bridges the ion transfer tube tothe MS inlet allowed for optimization of the ion signal. Both rigidtubing (metal conduit, and glass) as well as flexible (tygon tubing)were used in this example, all showing long distance ion transferabilities.

The LTP probe was utilized as a desorption ionization source with heliumas the discharge gas. This setup was initially used for ion transfer ofdrugs and explosives. 1.7 μg of cocaine and 2 μg of TNT were spottedonto separate glass slides and the slides were placed on a stage 4 ftfrom the inlet of the mass spectrometer. 4 ft of Tygon tubing was usedas the ion transfer member to transfer ions from the LTP probe to theinlet of the mass spectrometer. Data herein show successful detection ofthe cocaine in the positive MS/MS mode, as shown in FIG. 3. Data hereinalso show successful detection of the TNT in the negative MS/MS mode, asshown in FIG. 4.

The cocaine sample was then used over several hours for tests with 10 ftof metal conduit (FIG. 5), 15 ft of Tygon tubing, and also 30 ft ofTygon tubing, all resulting in positive confirmation of cocaine in thepositive MS/MS mode. It was also observed that the tubing did not haveto be straight, i.e., curved tubing still successfully transferred theions to the inlet of the mass spectrometer.

Example 2 Large Area and Long Distance Ion Transfer

Utilizing the apparatus shown in FIG. 2, large area analysis was done byusing three LTP probes to sample a large area. FIG. 6 shows the setup ofthe three LTP probes utilizing 4 ft (1.2 m) of Tygon tube for longdistance transfer. 1.7 μg of cocaine and 1 μg of atrazine were spottedonto a glass slide and analyzed via the LTP probe setup. The ellipticalshape outlined in black marker on the cardboard box is the approximatearea of detection for both 1.7 μg of cocaine and 1 μg of atrazineutilizing the long distance transfer apparatus, which is >>100 cm².Positive mode tandem mass spectrometry was used to confirm the moleculestransfer over the 4 ft distance.

An LTP large area funnel was coupled to the apparatus shown in FIG. 2via the 4 foot tygon tubing. Utilizing helium as the discharge gas, 2 μgof TNT on a glass slide were analyzed, shown in the top of FIG. 7. Thebottom of FIG. 7 shows the total ion current (TIC) of m/z 226(deprotonated TNT) transferred through 4 ft of Tygon tubing, clearlyshowing the detection of TNT when the funnel was placed over the sample.When the funnel was removed away from the sample the TIC was close tozero. A distance of >1″ could be maintained between the surface andglass slide and successful detection could occur while the area ofdetection was limited by the funnel area (33 cm²).

Example 3 Ion Transport with Desorption Electrospray Ionization (DESI)

The transport of ionic species in DESI sources was achieved over a longdistance (at least 1 m) by using a similar system as described in theExample above. However, the system was modified to remove the pump anduse the DESI sources as the gas flow generating device due to the highflow rate of gas generated from the DESI source. The ejecting gas from aDESI source, after impact with the desorption surface, was allowed topass through a long 0.25″ metal tube. The MS capillary was used tosample the ions at some suitable distance downstream of the gas flow.The schematic of this setup is shown ion FIG. 12. In comparison with apreviously reported development using a pressure tight enclosure(Venter, A.; Cooks, R. G. Anal. Chem., 2007, 79 (16), pp 6398-6403;United States Patent Application 2008/0156985), a large opening at thedistal end allows the DESI gas flow to exit to allow the formation of alaminar flow and to avoid the recirculation and turbulence inside theion transfer member.

Example 4 Long Distance Ion Transfer—DESI

In a set-up in which the gas flow generating device was the DESI source,the gas jet ejected from the DESI source itself was used for iontransport, i.e., long distance ion transport was achieved by using anion transport member without a pump. The gas jet emanating from DESIsource was used to transport ions.

Rhodamine ink was used as the analyte. A red ink spot was made on aglass slide using Sharpie ink, and the TIC during analysis was plottedagainst signal intensity (FIG. 13). Initially, the capillary was closeto the desorption surface (a few millimeters). As the distance betweenthe sample surface and the MS inlet was increased, the signal drop ratewas initially high, and the drop rate eventually slowed and then reacheda stable level at which an approximately constant signal intensity wasobtained irrespective of the distance between the sample and the MSinlet (FIG. 13).

Without being limited by any particular theory or mechanism of action,it is believed that the stable level was reached due to the inception ofa fully developed laminar flow a certain distance downstream of thedrift tube. Once the fully developed flow regime was achieved, the ionswere focused to the center of the ion transfer member and weretransmitted to the inlet of the mass spectrometer without any loss.Diffusion loss of ions was low. Hence, beyond a certain distance theloss of ions was very low. This technique of flow focusing using a 10 cmdrift tube of 0.24″ ID was also demonstrated with the Mini 10 instrument(See FIG. 21). Using a commercial CFD package (Ansys CFX), the flowevolution in the drift tube due to the DESI spray was calculated. It wasfound that the fully developed laminar flow regime was achieved in thedrift tube at about the same distance beyond which the signal fall ofrate was found to be low. (See FIG. 14).

Different drift tube lengths were used to collect spectrum of cocaineand the corresponding peak intensities were compared. Signal intensitieswith 5 cm, 10 cm, 15 cm, 20 cm, 50 cm, and 100 cm transfer tubes wererecorded using an LTQ mass spectrometer (Thermo Fisher Scientific,Inc.). The peak signal intensity achieved with each of the transfer tubewas plotted (See FIG. 20). These data show that the fall in signal withincreased sampling distance was not very significant. This is due tolaminar flow focusing of ions and consequent efficient transport. With a10 cm transfer tube, a very good signal for 10 μg of cocaine on a glassslide was detected with potential for even a 10 times lower detectionlimit (FIG. 15). It was observed that the relative intensity of thebackground peaks were lower for longer transfer tubes (FIG. 16). It wasconcluded that a longer drift tube filtered out background ions moreefficiently than a shorter drift tube, and thus a longer drift tubeassisted in obtaining the ions of interest from the sample. This wasakin to pre-concentration and selective analyte sampling(Cotte-Rodríguez et al, Chem. Commun., 2006, 2968-2970).

Example 5 Large Area

For the DESI configuration, a large area analysis was made byre-designing the drift tube and the sampling area. To increase thesampling area, a quarter inch tube was bent at a 45° angle at two sides,leaving a 4 cm central straight tube. The bottom of this portion was cutto create a sampling area. The schematic and drawing are shown in FIG.17. The new sampling surface had a 4 cm×3.5 mm sampling area. A thinsampling area was used to allow for a confined area for gas flow. In theDESI configuration, as external pump was not used to assist transfer ofions, rather the DESI gas jet was used to transport the ions through anarrow area for ensuring laminar flow development.

The effect of position of analyte in the sampling region on signalintensity was tested. Two analytes, MDMA(3,4-Methylenedioxymethamphetamine), and cocaine were used. The cocaineposition was fixed as shown by a circular shape and MDMA by triangle.Cocaine was closer to the DESI spray end. MDMA was closer to the MSsampling inlet. The pictorial representation of the experiment performedis shown in FIG. 18. Data show that the system was able to distinctlydetect both the cocaine and the MDMA of 1.5 μg (See mass spectra of FIG.19).

Example 6 Long Distance Ion Transfer—Low Temperature Plasma (LTP)

Mass spectrometers typically rely on the vacuum pumps of the system togenerate a vacuum to pull ions into the system that are generated froman ambient ionization source. This is problematic with a miniature massspectrometer because the vacuum pumps of such systems are much lesspowerful than those of standard mass spectrometer systems. It isparticularly difficult to couple an ambient ionization source with aminiature mass spectrometer due to the decreased vacuum power of such aninstrument. Systems of the invention generate an enlarged gas flow thatincreases efficiency of the movement of ions, and thus provides forefficient and focused transfer of ions generated from an ambientionization source and transfer to an inlet of a miniature massspectrometer.

A low temperature plasma (LTP) ambient ionization source, coupled with aportable mass spectrometer (Mini 10.5), was used for the determinationof melamine contamination in whole milk and related products (FIG. 22).Thermally assisted desorption and ionization of the analyte was achievedwith the LTP probe. The small size, low power consumption and capabilityfor direct sampling without pretreatment, makes LTP an appropriateionization method for use in conjunction with a handheld massspectrometer. The standard discontinuous atmospheric pressure interfaceused to connect atmospheric pressure ion sources to mini massspectrometers (Gao et al. Analytical Chemistry, 2008, 80, 4026-4032) wascoupled with an ion transfer member with supplementary pumping toincrease the ion transfer efficiency. Whole milk, fish, milk powder andother complex matrices spiked with melamine were placed on the glassslide close to the vacuum inlet and analyzed without samplepretreatment. Analysis rates of two samples per minute were achievedwhile levels of melamine as low as 250 ng/mL were detected in whole milkwith a linear dynamic range of 0.5-50 μg/mL and a relative standarddeviation of 7.6%˜16.2% (FIG. 23).

What is claimed is:
 1. A system for analyzing a sample, the systemcomprising: an ionizing source for converting molecules of a sample intosample ions; an ion analysis device; a pump external to the ion analysisdevice; an ion transfer member external the ion analysis device, whereinthe pump facilitates collection of the sample ions in the ion transfermember that is external the ion analysis device, which sample ions aretransferred through the ion transfer member to an inlet of the ionanalysis device.
 2. The system according to claim 1, wherein the pumpproduces a laminar gas flow without regions of recirculation thattransfers the sample ions through the ion transfer member to the inletof the ion analysis device.
 3. The system according to claim 1, whereinthe ionizing source comprises a gas inlet port and an electrodepositioned within the source to interact with a gas introduced throughthe gas inlet port and to generate a discharge that interacts with thesample to produce the sample ions.
 4. The system according to claim 1,wherein the sample ions are produced in a region at about atmosphericpressure.
 5. The system according to claim 1, wherein the ion transfermember is a tube.
 6. The system according to claim 5, wherein the tubeis composed of a rigid material.
 7. The system according to claim 6,wherein the rigid material is metal or glass.
 8. The system according toclaim 5, wherein the tube is straight.
 9. The system according to claim1, wherein the ionizing source is selected from the group consisting of:an electrospray ionization source, a nano-electrospray ionizationsource, an atmospheric pressure matrix-assisted laser desorptionionization source, an atmospheric pressure chemical ionization source, adesorption electrospray ionization source, an atmospheric pressuredielectric barrier discharge ionization source, an atmospheric pressurelow temperature plasma desorption ionization source, and anelectrospray-assisted laser desorption ionization source.
 10. The systemaccording to claim 1, wherein the ion analysis device is selected fromthe group consisting of a mass spectrometer, a handheld massspectrometer, and an ion mobility ion analysis device.
 11. The systemaccording to claim 10, wherein the mass spectrometer is selected fromthe group consisting of: a quadrupole ion trap, a rectilinear ion trap,a cylindrical ion trap, a ion cyclotron resonance trap, an orbitrap, asector, and a time of flight mass spectrometer.
 12. The system accordingto claim 1, further comprising a sample stage configured to hold thesample.
 13. The system according to claim 12, wherein the ionizingsource is arranged such that a distal tip of the ionizing source ispointed at the sample stage.
 14. A system for analyzing a sample, thesystem comprising: a sample stage configured to hold a sample; anionizing source arranged such that a distal tip of the ionizing sourceis pointed at the sample stage so that sample ions are generated fromthe sample; an ion analysis device; a pump external to the ion analysisdevice; and an ion transfer member external the ion analysis device,wherein the pump facilitates collection of the sample ions in the iontransfer member that is external the ion analysis device, which sampleions are transferred through the ion transfer member to an inlet of theion analysis device.
 15. The system according to claim 14, wherein theionizing source comprises a gas inlet port and an electrode positionedwithin the source to interact with a gas introduced through the gasinlet port and to generate a discharge that interacts with the sample toproduce the sample ions.
 16. The system according to claim 14, whereinthe sample ions are produced in a region at about atmospheric pressure.17. The system according to claim 14, wherein the ion transfer member isa tube.
 18. The system according to claim 17, wherein the tube iscomposed of a rigid material.
 19. The system according to claim 18,wherein the rigid material is metal or glass.